Third-party CD4+ invariant natural killer T cells protect from murine GVHD lethality

Schneidawind, Dominik; Baker, Jeanette; Pierini, Antonio; Buechele, Corina; Luong, Richard; Meyer, Everett; Negrin, Robert S.

doi:10.1182/blood-2014-11-612762

Cited by 75 publications

(71 citation statements)

References 59 publications

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“…Murine models have identified CD4+ invariant NKT cells (iNKT) as key regulators of Treg expansion and function in vivo . (148–150). In HCT patients, Treg number in the stem cell product inversely correlated with the subsequent development of acute GVHD (151, 152).…”

Section: A Three Phase Model For Chronic Gvhd Biologymentioning

confidence: 99%

The Biology of Chronic Graft-versus-Host Disease: A Task Force Report from the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease

Cooke

Luznik

Sarantopoulos

et al. 2017

Biology of Blood and Marrow Transplantation

360

322

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Summary Chronic graft-versus-host disease (GVHD) is the leading cause of late, non-relapse, mortality and disability in allogeneic hematopoietic cell transplantation (HCT) patients and a major obstacle to improving outcomes. Chronic GVHD biology remains enigmatic, but understanding the underpinnings of the immunologic mechanisms responsible for the initiation and progression of disease is fundamental to developing effective prevention and treatment strategies. The goals of this task force review are as follows: Summarize the current “state-of-the-science” regarding pathogenic mechanisms of chronic GVHD and critical knowledge gaps.Develop working hypotheses/overriding concepts for chronic GVHD development.Define the usefulness of current preclinical models to test working hypotheses and ultimately discover and develop new therapeutic strategies.Identify shortcomings of preclinical models, and define criteria for the creation of additional models to address these limitations. This document is intended as a review of our understanding of chronic GVHD biology and therapies resulting from preclinical studies, and as a platform for developing innovative clinical strategies to prevent and treat chronic GVHD.

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Section: A Three Phase Model For Chronic Gvhd Biologymentioning

confidence: 99%

The Biology of Chronic Graft-versus-Host Disease: A Task Force Report from the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease

Cooke

Luznik

Sarantopoulos

et al. 2017

Biology of Blood and Marrow Transplantation

360

322

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“…Thus, we have explored an alternative immune regulatory population, iNKT cells, that are not exquisitely IL-2 sensitive and are highly effective in limited cell numbers in preventing acute GVHD (aGVHD). [4][5][6] iNKT cells have immune regulation function, 7 conferred by the rapid production of immune regulatory cytokines such as IL-4 and IL-10, 8,9 and promote Treg expansion, perhaps through a myeloid cell intermediate. 5,10 iNKT deficiency has been linked to autoimmune diseases (eg, type 1 diabetes, rheumatoid arthritis, and lupus).…”

Section: Introductionmentioning

confidence: 99%

Invariant natural killer T cells ameliorate murine chronic GVHD by expanding donor regulatory T cells

Paz²,

Thangavelu³

et al. 2017

Blood

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• Low doses of donor iNKT infusion prevent and reverse murine cGVHD.• iNKT efficacy in treating established cGVHD is dependent on donor Treg expansion.Chronic graft-versus-host-disease (cGVHD) can cause multiorgan system disease, typically with autoimmune-like features, resulting in high mortality and morbidity caused by treatment limitations. Invariant natural killer T cells (iNKTs), a small population characterized by expression of a semi-invariant T-cell receptor, rapidly produce copious amounts of diverse cytokines on activation that exert potent immune regulatory function.Here, we show that iNKTs are significantly reduced in a cGVHD murine model that recapitulates several aspects of autoimmunity and organ fibrosis observed in patients with cGVHD. Low iNKT infused doses effectively prevented and, importantly, reversed established cGVHD, as did third-party iNKTs. iNKTs suppressed the autoimmune response by reducing the germinal center (GC) reaction, which was associated with an increase in total Tregs and follicular Tregs (Tfr) that control the GC reaction, along with pathogenic antibody production. Treg depletion during iNKT infusions completely abolished iNKT efficacy in treating cGVHD. iNKT cell interleukin 4 production and GC migration were critical to cGVHD reversal. In vivo stimulation of iNKT cells by a-galactosyl-ceramide was effective in both preventing and treating cGVHD. Together, this study demonstrates iNKT deficiency in cGVHD mice and highlights the key role of iNKTs in regulating cGVHD pathogenesis and as a potentially novel prophylactic and therapeutic option for patients with cGVHD. (Blood. 2017;129(23):3121-3125)

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“…However, although GVHD is reduced, the effect on T cells that reject allogeneic leukemia cells needs to be considered, making this approach most interesting for patients undergoing allo-HCT for nonmalignant diseases. Other lines of promising future translation for aGVHD are: besides others, natural killer T-cell therapy, 121 IL-22 proteins that help to protect the intestinal stem cell mice, 122 and modifications of the microbiome. 123 cGVHD promising approaches include among others: Syk inhibitors that were shown to reduce disease severity in the mouse model 124,125 and are currently developed into a clinical trial, BTK inhibition, targeting of IL-21, and B-cell activating factor that may help to control this major complication after allo-HCT.…”

Section: Novel Promising Targets and Approachesmentioning

confidence: 99%

Preclinical models of acute and chronic graft-versus-host disease: how predictive are they for a successful clinical translation?

Zeiser

Blazar

2016

Blood

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Despite major advances in recent years, graft-versus-host disease (GVHD) remains a major life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT). To improve our therapeutic armory against GVHD, preclinical evidence is most frequently generated in mouse and large animal models of GVHD. However, because every model has shortcomings, it is important to understand how predictive the different models are and why certain findings in these models could not be translated into the clinic. Weaknesses of the animal GVHD models include the irradiation only-based conditioning regimen, the homogenous donor/recipient genetics in mice, canine or non-human primates (NHP), anatomic site of T cells used for transfer in mice, the homogenous microbial environment in mice housed under specific pathogen-free conditions, and the lack of pharmacologic GVHD prevention in control groups. Despite these major differences toward clinical allo-HCT, findings generated in animal models of GVHD have led to the current gold standards for GVHD prophylaxis and therapy. The homogenous nature of the preclinical models allows for reproducibility, which is key for the characterization of the role of a new cytokine, chemokine, transcription factor, microRNA, kinase, or immune cell population in the context of GVHD. Therefore, when carefully balancing reasons to apply small and large animal models, it becomes evident that they are valuable tools to generate preclinical hypotheses, which then have to be rigorously evaluated in the clinical setting. In this study, we discuss several clinical approaches that were motivated by preclinical evidence, novel NHP models and their advantages, and highlight the recent advances in understanding the pathophysiology of GVHD. (Blood. 2016; 127(25):3117-3126)

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Third-party CD4+ invariant natural killer T cells protect from murine GVHD lethality

Abstract: Key Points Low doses of adoptively transferred third-party CD4+ iNKT cells protect from lethal GVHD while preserving graft-versus-tumor effects. Third-party CD4+ iNKT cells are rejected early after transplantation yet protect from GVHD lethality through donor Tregs.

Cited by 75 publications

References 59 publications

The Biology of Chronic Graft-versus-Host Disease: A Task Force Report from the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease

The Biology of Chronic Graft-versus-Host Disease: A Task Force Report from the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease

Invariant natural killer T cells ameliorate murine chronic GVHD by expanding donor regulatory T cells

Preclinical models of acute and chronic graft-versus-host disease: how predictive are they for a successful clinical translation?

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